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Full-profile pharmacokinetics, anticancer activity and toxicity of an extended release trivalent PEGylated irinotecan prodrug

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Acta Pharmaceutica Sinica B 2023年第8期13卷 3444-3453页

作者： Shiwen Song Dong Sun Hong Wang Jinliang Wang Huijing Yan Xuan Zhao john paul fawcett Xin Xu Deqi Cai Jingkai Gu Research Center for Drug Metabolism School of Life SciencesJilin UniversityChangchun 130012China Center for Food and Drug Inspection of NMPA Changchun 130012China Jen Kem Technology Co. Ltd.Tianjin 300450China State Key Laboratory of Supramolecular Structure and Materials College of ChemistryJilin UniversityChangchun 130012China Beijing Institute of Drug Metabolism Beijing 102209China

Irinotecan is an anticancer topoisomerase I inhibitor that acts as a prodrug of the active metabolite,***,the limited utility of irinotecan is attributed to its pH-dependent stability,short half-life and dose-limiting *** address this problem,a novel trivalent PEGylated prodrug(PEG-[Irinotecan]3)has been synthesized and its full-profile pharmacokinetics,antitumor activity and toxicity compared with those of *** results show that after intravenous administration to rats,PEG-[Irinotecan]3 undergoes stepwise loss of irinotecan to form PEG-[Irinotecan]3-x(x=1,2)and PEG-[linker]during which time the released irinotecan undergoes conversion to *** compared with conventional irinotecan,PEG-[Irinotecan]3 displays extended release of irinotecan and efficient formation of SN-38 with significantly improved AUC and *** a colorectal cancer-bearing model in nude mice,the tumor concentrations of irinotecan and SN-38 produced by PEG-[Irinotecan]3 were respectively 86.2 and 2293 times higher at 48 h than produced by *** summary,PEG-[Irinotecan]3 displays superior pharmacokinetic characteristics and antitumor activity with lower toxicity than *** supports the view that PEG-[Irinotecan]3 is a superior anticancer drug to irinotecan and it has entered the phaseⅡtrial stage.

关键词： Irinotecan SN-38 Trivalent PEGylated irinotecan Prodrug Full-profile pharmacokinetics

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The biological fate of the polymer nanocarrier material monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid)in rat

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Acta Pharmaceutica Sinica B 2021年第4期11卷 1003-1009页

作者： Xiangjun Meng Zhi Zhang Jin Tong Hui Sun john paul fawcett Jingkai Gu Research Center for Drug Metabolism School of Life SciencesJilin UniversityChangchun 130012China Beijing Institute of Drug Metabolism Beijing 102209China School of Pharmaceutical Sciences Tsinghua UniversityBeijing 100084China

Monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid)(PEG-PLA)is a typical amphiphilic di-block copolymer widely used as a nanoparticle carrier(nanocarrier)in drug *** the in vivo fate of PEG-PLA is required to evaluate its overall safety and promote the development of PEG-PLA-based nanocarrier drug delivery ***,acquiring such understanding is limited by the lack of a suitable analytical method for the bioassay of *** this study,the pharmacokinetics,biodistribution,metabolism and excretion of PEG-PLA were investigated in rat after intravenous *** results show that unchanged PEG-PLA is mainly distributed to spleen,liver,and kidney before being eliminated in urine over 48 h mainly(>80%)in the form of its PEG *** study provides a clear and comprehensive picture of the in vivo fate of PEG-PLA which we anticipate will facilitate the scientifc design and safety evaluation of PEG-PLA-based nanocarrier drug delivery systems and thereby enhance their clinical development.

关键词： Monomethoxy poly(ethylene glycol)-block-poly(D,L-lactic acid) Polymer Nanocarrier material Pharmacokinetics Biodistribution Metabolism Excretion Rat

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Disposition and fate of polyoxyethylene glycerol ricinoleate as determined by LC-Q-TOF MS coupled with MS^(ALL),SWATH and HR MS/MS techniques

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Chinese Chemical Letters 2021年第10期32卷 3237-3240页

作者： Ruifeng Bai Dong Sun Yuqin Shan Zhiqiong Guo Dafeng Chu john paul fawcett Jingkai Gu Center for Drug Metabolism Research School of Life SciencesJilin UniversityChangchun 130012China

Polyoxyethylene glycerol ricinoleate(PGR) serves as a solubilizer/emulsifier that is commonly used in pharmaceutical formulations despite being associated with severe anaphylactoid hypersensitivity *** EL?(CrEL) is the most representative PGR produced from reacting ethylene oxide with castor *** help clarify the cause of side effects and potentially improve the safety of PGR-based drug delivery vehicle,we have developed separate but related analytical methods for the quantitation of CrEL and its main metabolites,glycerol ethoxylate(GE) and ricinoleic acid(RA).Since CrEL and GE are highly disperse mixtures of polymers that are not amenable to analysis by conventional liquid chromatographytandem mass spectrometry(LC-MS/MS),we used liquid chromatography-triple-quadrupole-time-of-flight mass spectrometry(LC-Q-TOF MS) combined with product ion data acquisition by MSALLand sequential window acquisition of all theoretical fragments mass spectrometry(SWATH MS),respectively to perform the *** contrast,RA is a single molecular entity that could be readily analyzed using conventional LC-HR MS/*** of specific fragment ions for CrEL,GE,RA and their internal standards enabled a precise quantitation of such a complex analytes system in rat plasma after a single and simple sample preparation *** validation indicated linearity for CrEL,GE and RA over the concentration ranges 0.2~20.0 μg/mL,0.1~10.0 μg/mL and 0.1~20.0 μg/m L,respectively with satisfactory results for other validation parameters.A subsequent pharmacokinetic study involving single intravenous 200 mg/kg injections of CrEL to rats showed the methods enable comprehensive and high throughput quantitation of CrEL and its metabolites in a biological *** combination of assays provides effective application in investigating the cause of the hypersensitivity reaction of PGR and potentially to improve its safety for using as a vehicle in drug formulations.

关键词： Polyoxyethylene glycerol ricinoleate Cremophor EL LC-Q-TOF MS Glycerol ethoxylate Ricinoleic acid

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Impact of molecular weight on the mechanism of cellular uptake of polyethylene glycols(PEGs) with particular reference to P-glycoprotein

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Acta Pharmaceutica Sinica B 2020年第10期10卷 2002-2009页

作者： Tingting Wang Yingjie Guo Yang He Tianming Ren Lei Yin john paul fawcett Jingkai Gu Huimin Sun Clinical Laboratory First HospitalJilin UniversityChangchun 130061China Research Institute of Translational Medicine First HospitalJilin UniversityChangchun 130061China Research Center for Drug Metabolism College of Life ScienceJilin UniversityChangchun 130012China Department of Pharmaceutical Sciences and Experimental Therapeutics College of PharmacyUniversity of IowaIowa City IA 52242USA Beijing Institute of Drug Metabolism Beijing 102209China National Institutes for Food and Drug Control Beijing 100050China

Polyethylene glycols(PEGs)in general use are polydisperse molecules with molecular weight(MW)distributed around an average value applied in their designation e.g.,PEG *** research has shown that PEGs can act as P-glycoprotein(P-gp)inhibitors with the potential to affect the absorption and efflux of concomitantly administered ***,questions related to the mechanism of cellular uptake of PEGs and the exact role played by P-gp has not been *** this study,we examined the mechanism of uptake of PEGs by MDCK-mock cells,in particular,the effect of MW and interaction with P-gp by MDCK-hMDRl and A549 *** results show that:(a)the uptake of PEGs by MDCK-hMDR1 cells is enhanced by P-gp inhibitors;(b)PEGs stimulate P-gp ATPase activity but to a much lesser extent than verapamil;and(c)uptake of PEGs of low MW(5000 Da)occurs by a combination of passive diffusion and caveolae-mediated *** findings suggest that PEGs can engage in P-gp-based drug interactions which we believe should be taken into account when using PEGs as excipients and in PEGylated drugs and drug delivery systems.

关键词： P-gp PEGs P-gp-substrate Passive diffusion Endocytosis

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Protein target discovery of drug and its reactive intermediate metabolite by using proteomic strategy

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Acta Pharmaceutica Sinica B 2012年第2期2卷 126-136页

作者： Lianghai Hu john paul fawcett Jingkai Gu Clinical Pharmacology Center Institute for Translational MedicineNorman Bethune First HospitalJilin UniversityChangchun 130021China Research Center for Drug Metabolism College of Life ScienceJilin UniversityChangchun 130023China School of Pharmacy University of OtagoPO Box 56DunedinNew Zealand

Identifying protein targets of bioactive compounds is an effective approach to discover unknown protein functions,identify molecular mechanisms of drug action,and obtain information for optimization of lead *** the same time,metabolic activation of a drug can lead to ***,it is very important to systemically characterize the drug and its reactive *** spectrometry-based proteomic approach has emerged as the most efficient to study protein functions and *** review will discuss method development for the drug target discovery and the application in different fields including the drug toxicity mechanism caused by reactive metabolites.

关键词： Drug target Reactive metabolite Proteomics Mass spectrometry

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The Decarbonization of Construction—How Can Alkali-Activated Materials Contribute?

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Engineering 2024年第6期37卷 18-21页

作者： john L.Provis Susan A.Bernal Zuhua Zhang Department of Materials Science and Engineering University of SheffieldSheffield S13JDUK paul Scherrer Institut Villigen PSI 5232Switzerland School of Civil Engineering University of LeedsLeeds LS29JTUK School of Materials Sciences and Engineering Tongji UniversityShanghai 201804China

*** and context Enormous emphasis is currently being paid to the decarbonization of the global built environment as a leading priority for the engineering community and related industrial sectors[1].One of the main contributors to the overall emissions footprint of the built environment-and thus a cornerstone of efforts to achieve decarbonization-is the emissions profile of construction materials during their production and *** cement and concrete sector is the largest-volume contributor to the emissions incurred in meeting the world’s construction material needs and is therefore targeted in the discussion of the deep,rapid decarbonization that must be achieved in order to minimize irreversible damage to the Earth and its ecosystems.

关键词： Alkali corners irreversible

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Biological fate and interaction with cytochromes P450 of the nanocarrier material,D-α-tocopheryl polyethylene glycol 1000 succinate

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Acta Pharmaceutica Sinica B 2022年第7期12卷 3156-3166页

作者： Tianming Ren Runzhi Li Liqiang Zhao J.paul fawcett Dong Sun Jingkai Gu Research Center for Drug Metabolism School of Life SciencesJilin UniversityChangchun 130012China State Key Laboratory of Supramolecular Structure and Materials Jilin UniversityChangchun 130012China Beijing Institute of Drug Metabolism Beijing 102209China

D-a-Tocopheryl polyethylene glycol 1000 succinate(TPGS,also known as vitamin E-TPGS)is a biodegradable amphiphilic polymer prepared by esterification of vitamin E with polyethylene glycol(PEG)*** is approved by the US Food and Drug Administration(FDA)and has found wide application in nanocarrier drug delivery systems(NDDS).Fully characterizing the in vivo fate and pharmacokinetic behavior of TPGS is important to promote the further development of TPGS-based ***,to date,a bioassay for the simultaneous quantitation of TPGS and its metabolite,PEG1000,has not been *** the present study,we developed such an innovative bioassay and used it to investigate the pharmacokinetics,tissue distribution and excretion of TPGS and PEG1000 in rat after oral and intravenous *** addition,we evaluated the interaction of TPGS with cytochromes P450(CYP450s)in human liver *** results show that TPGS is poorly absorbed after oral administration with very low bioavailability and that,after intravenous administration,TPGS and PEG1000 are mainly distributed to the spleen,liver,lung and kidney before both being slowly eliminated in urine and feces as *** vitro studies show the inhibition of human CYP450 enzymes by TPGS is limited to a weak inhibition of ***,our results provide a clear picture of the in vivo fate of TPGS which will be useful in evaluating the safety of TPGS-based NDDS in clinical use and in promoting their further development.

关键词： TPGS LC-MS/MS Nanocarrier materials Pharmacokinetics Tissue distribution Metabolism Excretion Cytochrome P450

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Quantitative Applications of Weather Satellite Data for Nowcasting:Progress and Challenges

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Journal of Meteorological Research 2024年第3期38卷 399-413页

作者： Jun LI Jing ZHENG Bo LI Min MIN Yanan LIU Chian-Yi LIU Zhenglong LI Wpaul MENZEL Timothy J.SCHMIT john L.CINTINEO Scott LINDSTROM Scott BACHMEIER Yunheng XUE Yayu MA Di DI Han LIN Innovation Centre for Fengyun Meteorological Satellite(FYSIC) National Satellite Meteorological CentreChina Meteorological AdministrationBeijing100081China School of Atmospheric Sciences and Guangdong Province Key Laboratory for Climate Change and Natural Disaster Studies Sun Yat-sen University and Southern Laboratory of Ocean Science and EngineeringZhuhai519082China Key Laboratory of Geographic Information Science(Ministry of Education) East China Normal UniversityShanghai200241China Research Center for Environmental Changes Academia SinicaTaipei11529China Cooperative Institute for Meteorological Satellite Studies University of Wisconsin-MadisonMadisonWI53706USA Sensors and Calibration Branch STAR/NESDISMadisonWI53706USA Wuxi University Wuxi214105China School of Computer Science Chengdu University of Information TechnologyChengdu610225China Collaborative Innovation Center on Forecast and Evaluation of Meteorological Disasters Nanjing University of Information Science&TechnologyNanjing210044China Key Laboratory of Spatial Data Mining and Information Sharing of Ministry of Education National and Local Joint Engineering Research Center of Satellite Geospatial Information TechnologyFuzhou UniversityFuzhou350108China

Monitoring and predicting highly localized weather events over a very short-term period,typically ranging from minutes to a few hours,are very important for decision makers and public *** these events usually relies on radar observations through monitoring and *** advanced high-resolution imaging and sounding observations from weather satellites,nowcasting can be enhanced by combining radar,satellite,and other data,while quantitative applications of those data for nowcasting are advanced through using machine learning *** applications include monitoring the location,impact area,intensity,water vapor,atmospheric instability,precipitation,physical properties,and optical properties of the severe storm at different stages(pre-convection,initiation,development,and decaying),identification of storm types(wind,snow,hail,etc.),and predicting the occurrence and evolution of the *** observations can provide information on the environmental characteristics in the preconvection stage and are very useful for situational awareness and storm *** paper provides an overview of recent progress on quantitative applications of satellite data in nowcasting and its challenges,and future perspectives are also addressed and discussed.

关键词： weather satellite quantitative applications nowcasting pre-convection

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Influence of inter-grain cementation stiffness on the effective elastic properties of porous Bentheim sandstone

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Journal of Rock Mechanics and Geotechnical Engineering 2023年第3期15卷 573-583页

作者： Bin Chen Jiansheng Xiang john-paul Latham Department of Earth Science and Engineering Faculty of EngineeringImperial College LondonLondonSW72BXUK

Effective elastic properties of porous media are known to be significantly influenced by *** this paper,we investigated the influence of another critical factor,the inter-grain cementation stiffness,on the effective elastic properties of a granular porous rock(Bentheim sandstone)using an advanced numerical workflow with realistic rock microstructure and a theoretical ***,the disparity between the experimentally tested elastic properties of Bentheim sandstone and the effective elastic properties predicted by empirical equations was ***,a micro-computed tomography(CT)-scan based approach was implemented with digital imaging software AVIZO to construct the 3D(three-dimensional)realistic microstructure of Bentheim *** microstructural model was imported to a mechanics solver based on the 3D finite element model with inter-grain boundaries modelled by cohesive *** simulations were run to test the effective elastic properties for different shear and normal intergrain cementation ***,a relation between the macroscale Young’s modulus and inter-grain cementation stiffness was derived with a theoretical model which can also account for porosity *** the numerical and theoretical results indicate the influence of the inter-grain cementation stiffness,on the effective elastic properties is significant for porous *** calibrated normal and shear stiffnesses at the inter-grain boundaries are 1.2×10^(5) and 4×10^(4) GPa/m,respectively.

关键词： Porous sandstone Cohesive finite element model Grain-based model Rock microstructure Micro-computed tomography(CT)

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A randomized controlled trial of Promoting Physical Activity in Regional and Remote Cancer Survivors(PPARCS)

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Journal of Sport and Health Science 2024年第1期13卷 81-89页

作者： Sarah J.Hardcastle Chloe Maxwell-Smith Vinicius Cavalheri Terry Boyle Marta Leyton Román Cameron Platell Michael Levitt Christobel Saunders Frank Sardelic Sophie Nightingale Jacob McCormick Craig Lynch paul A.Cohen Max Bulsara Dana Hince Sport and Physical Activity Research Centre Sheffield Hallam UniversitySheffieldS102BPUK Institute for Health Research The University of Notre DameFremantleWA 6959Australia Curtin School of Population Health Curtin UniversityPerthWA 6845Australia Curtin School of Allied Health Curtin UniversityPerthWA 6845Australia Allied Health South Metropolitan Health ServiceMurdochWA 6150Australia Australian Centre for Precision Health University of South AustraliaAdelaideSA 5001Australia Department of Didactics of Musical Plastic and Body ExpressionUniversity of ExtremaduraCaceres 10071Spain St.john of God Subiaco Hospital PerthWA 6008Australia Department of Surgery University of MelbourneMelbourneVIC 3010Australia Tamara Private Hospital TamworthNSW 2340Australia Peter MacCallum Cancer Centre MelbourneVIC 3000Australia College of Health and Medicine Australian National UniversityCanberraACT 2600Australia Division of Obstetrics and Gynaecology Medical SchoolUniversity of Western AustraliaPerthWA 6009Australia

Background:Physical activity(PA)is important for cancer *** of remotely delivered interventions are needed to assist in reaching under-served non-metropolitan cancer *** objective of this study was to ascertain whether wearable technology,coupled with health coaching was effective in increasing PA in breast and colorectal cancer survivors living in regional and remote areas in ***:Cancer survivors from 5 states were randomized to intervention and control *** participants were given a Fitbit Charge 2TMand received up to 6 telephone health coaching *** participants received PA print *** assessments at baseline and 12 weeks measured moderate-to-vigorous PA(MVPA),light PA,and sedentary ***:Eighty-seven participants were recruited(age=63±11 years;74(85%)female).There was a significant net improvement in MVPA of 49.8 min/week,favoring the intervention group(95%confidence interval(95%CI):13.6-86.1,p=0.007).There was also a net increase in MVPA bouts of 39.5 min/week(95%CI:11.9-67.1,p=0.005),favoring the intervention *** groups improved light PA and sedentary behavior,but there were no between-group ***:This’s the first study to demonstrate that,when compared to standard practice(i.e.,PA education),a wearable technology intervention coupled with distance-based health coaching,improves MVPA in non-metropolitan cancer *** results display promise for the use of scalable interventions using smart wearable technology in conjunction with phone-based health coaching to foster increased PA in geographically disadvantaged cancer survivors.

关键词： Behavior change Exercise Health disparities Oncology Wearable technology

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